What is prodrug!

Prodrugs are masked forms of active drugs that are designed to be activated after an enzymatic or chemical reaction once they have been administered into the body. Prodrugs are considered to be inactive or at least significantly less active than the released drugs; therefore, salts of active agents and drugs, whose metabolites contribute to the overall pharmacological response, are not included in this definition (Fig.1). The rationale behind the use of prodrugs is generally to optimize the so-called “drug-like” properties. During the past years, the pharmaceutical sciences have undergone a molecular revolution; no longer relying on empirical fitting based on plasma levels, the modern ADME (absorption, distribution, metabolism and excretion) research considers molecular/cellular factors, such as membrane transporters and cellular enzyme expression and distribution. This molecular revolution dramatically influenced today’s drug design and delivery at large, and the prodrug approach in particular. The prodrug strategy has been used to increase the selectivity of drugs for their intended target. This can not only improve the efficacy of the drug but also decrease systemic and/or unwanted tissue/organ-specific toxicity. Development of a prodrug with improved properties may also represent a life-cycle management opportunity. Figure 1. Adrien Albert first introduced the term “pro-drug” in 1958. A few decades later, he apologized for having invented such an inaccurate term, because “predrug” would have been a more descriptive term. However, by that time, the original version was used too widely to be changed. Nonetheless, the prodrug concept has been invented long before Albert’s publication. The first intentionally designed prodrug is most probably methenamine (or hexamine), which was introduced 1899 by Schering. At the same time, Bayer introduced aspirin (acetylsalicylic acid) as a less irritating form of the anti-inflammatory agent sodium salicylate. Many decades elapsed until Bayer introduced their next prodrug, the antibiotic prontosil, in 1935. However, prontosil was not intentionally developed as a prodrug, because only later in the same year was it found to release an active agent, para-aminophenyl sulfonamide, by reductive enzymes. In a similar way, Roche discovered the prodrug activity of the antituberculosis drug isoniazid more than 40 years after its introduction in 1952. Since the 1960s there has been an explosive increase in the use of prodrugs in drug discovery and development. The beginning of 21st century, when property based drug design became an essential part of the drug discovery and development process, has been a time of real breakthroughs in prodrugs. Figure 2. The molecular revolution has allowed for a modern prodrug approach to emerge, in which pro-moieties are covalently attached to the molecule of interest to selectively target certain transporters or enzymes. This modern strategy offers remarkable potential for improving drug bioavailability and selectivity of poorly absorbed drug molecules. 1. Targeting Transporters in Prodrug Design 2. Targeting Enzymes in Prodrug Design Prodrugs can be classified taking in consideration their chemical structure, mechanism of activation and the modified functional groups. 1. By chemical criteria can be distinguished: conventional prodrugs - obtained by chemical derivatization bio precursors – those substances which were not designed by conscious planning, but their activation in the body occurs through chemical reactions. Such prodrug is lovastatin, some vitamins (e.g. B1, B6), which after phosphorylation or oxidation (e.g. vitamin D) are exercising their physiological role. drug delivery systems: – drug - polymer conjugates, where the drug is binding to a macromolecule that favors its transport – drug-antibody conjugates, target delivery is performed by antibody. 2. Prodrugs can be classified into two major types, based on how the body converts the prodrug into the final active drug form: Type I prodrugs are bioactivated inside the cells (intracellularly). Examples of these are anti-viral nucleoside analogs that must be phosphorylated and the lipid-lowering statins. Type II prodrugs are bioactivated outside cells (extracellularly), especially in digestive fluids or in the body's circulatory system, particularly in the blood. Examples of Type II prodrugs are salicin (described above) and certain antibody-, gene- or virus-directed enzyme prodrugs used in chemotherapy or immunotherapy. Classification by activation mechanism is based on the types of reactions that result the active form, as: hydrolysis (ester, amide, imide, ether etc.); oxidation; reduction; other reactions Figure 3. Prodrugs in cancer therapy The effectiveness of cancer chemotherapy would increase if the active substance would reach the targeted tumor cell without damaging body cells. Tumor specificity may be achieved in many ways, such as by use of enzymes or transporters, or the development of prodrug-antibody which is selectively recognized by tumor cells. It is an advantage if the preparation can be administered also orally. An example of success is capecitabine, a prodrug of 5-fluorouracil (5-FU), that requires a cascade of three enzymes for the bioconversion to the active drug. The first degradation takes place in the liver by carboxyl esterase, when pentyl alcohol, of lipophilic character, is eliminated. This is followed by deamination by cytidine deaminase enzyme present in both the liver and tumor cells, followed by selective release of 5-FU in the tumor cells under the action of thymidine phosphorylase, which shows much higher activity in tumor cells than in normal cells. The prodrug is absorbed rapidly and almost completely from the gastrointestinal tract and provides high concentration of 5-FU in targeted tumor cell. Capecitabine is used orally in metastatic colon cancer and in combination therapy in other types of cancer. by Babayeva N. References: https://www.researchgate.net/publication/5633050_Prodrugs_Design_and_clinical_applications https://www.ncbi.nlm.nih.gov/pubmed/25317578 https://www.researchgate.net/publication/309383341_Prodrug_Strategy_in_Drug_Development https://www.ncbi.nlm.nih.gov/pubmed/21737530 https://en.wikipedia.org/wiki/Prodrug